A review of the ethnomedicinal, phytochemical, and pharmacological properties of the Ferulago genus based on Structure-Activity Relationship (SAR) of coumarins

Abstract

Background: The Ferluago W.D.J. Koch genus includes 48 accepted perennial herbs that are distributed in the Mediterranean region, Southeast Europe, Central and Middle East of Asia. These plants are widely used in folk and conventional medicine due to their biological benefits such as anti-microbial, anti-inflammatory, anti-cancer, and immunomodulatory properties. Conducting a comprehensive review based on the structure activity relationships (SARs) of the coumarins, which has not been previously documented, can lead to a better insight into the genus Ferulago and its beneficial therapeutic activities.

Methods: This review covers literature from 1969 to 2023, were collected from various scientific electronic databases to review phytochemical, pharmacological, and ethnopharmacological data of Ferulago species, as well as latest information on the SAR of reported coumarins from this genus.

Results: Phytochemical studies showed that the biological actions of this genus are mediated by the reported specialized metabolites, such as coumarins and flavonoids. Simple coumarins, prenylated coumarins, furanocoumarins, and pyranocoumarins are the largest subclasses of coumarins found in diverse Ferulago species, which have discussed the biological effects of them with a focus on the Structure-Activity Relationship (SAR). For example, prenylated coumarins have shown potential leishmanicidal and anti-neuropsychiatric effects when substituted with a prenyl group at the 7-hydroxy, as well as the C₆ and C₈ positions in their scaffold. Similarly, furanocoumarins exhibit varied biological activities such as anti-inflammatory, anti-proliferative, and anti-convulsant effects. Modifying substitutions at the C₅ and C₆ positions in furanocoumarins can enhance these activities.

Conclusion: This study conducted a comprehensive review of all available information on the phytochemical and pharmacological characteristics of Ferulago species. Given the high occurrence of coumarins in this genus, which exhibit potential anti-Alzheimer and anti-microbial properties, it presents promising new therapeutic avenues for addressing these common issues. Further investigation is needed to understand the molecular-level mechanisms of action and to explore their clinical applications.

Keywords: Ferluago; Anti-Alzheimer; Anti-cancer; Apiaceae; Coumarins; Phytochemistry.

Fig. 1

The Ferulago species in the flowering stage; a F. trachycarpa, b F. humilis [39, 40]

Fig. 2

Schematic biosynthetic pathways of coumarins

Fig. 3

SAR study of simple coumarins

Fig. 4

SAR study of C-prenylcoumarins and O-prenylcoumarins

Fig. 5

SAR study of linear furanocoumarins

Fig. 6

SAR study of linear pyranocoumarins

Fig. 7

Various pharmacological studies on Ferulago spp

Fig. 8

Anti-microbial; Phenolic compounds disrupt lipid arrangements, denature proteins, and increase membrane permeability which lead to membrane breakdown. Cytotoxic; The hexane extract derived from F. angulata has demonstrated cytotoxic effects by inducing apoptosis through the intrinsic pathway and inhibiting proliferation via cell cycle arrest. This extract led to the downregulation of Bcl-2 and upregulation of Bax, p21, and p27, resulting in G1 phase cell cycle arrest. Oxypeucedanin methanolate was found to enhance the expression of mRNA of Bax and Caspase-3 while reducing Bcl-2 expression in A549 cells, indicating its potential pro-apoptotic effects. Moreover, grandivittin was observed to increase the expression of Bax, P53, caspase 3, and caspase 9 genes in A549 cells, while concurrently diminishing Bcl-2 gene expression. Neuroprotective; Semi-polar extracts from Ferulago species exhibit stronger inhibition of BChE compared to AChE. Specific compounds like xanthotoxin, siol anisate, and umbelliprenin show varying levels of inhibition against AChE. Similarly, felamidin, peucedanol, and prantschimgin inhibit BChE activity to varying degrees. MeOH extract from F. angulata demonstrates potential neuroprotective effects against amyloid-β (Aβ)-induced toxicity. It reduces the production of reactive oxygen species (ROS), prevents Aβ-induced reduction of glutathione peroxidase (GPx) activity, and decreases the increase in AChE activity, which are all associated with Aβ toxicity. Monoamine oxidase (MAO) enzymes, particularly MAO-B, are implicated in the accumulation of Aβ. The hydroalcoholic extract of F. angulata inhibits both MAO-A and MAO-B in a non-selective manner. Osthole is implicated in protecting against neurodegenerative disorders by activating neuroprotective signaling pathways such as the brain-derived neurotrophic factor (BDNF)/Trk and phosphoinositide 3-kinase (PI3K)/Akt pathways. Anti-oxidant; The hydroalcoholic extract derived from F. angulata has been demonstrated to enhance the activity of Catalase (CAT), elevate the levels of Superoxide dismutase (SOD) and GPx, subsequently leading to a reduction in plasma levels of Malondialdehyde (MDA), a commonly employed marker for assessing lipid peroxidation resulting from oxidative stress. SOD assumes a pivotal role as a catalyst in the dismutation of superoxide radicals (O2⁻) into hydrogen peroxide (H₂O₂). Despite being less reactive than superoxide radicals, excessive accumulation of hydrogen peroxide can still induce cellular damage. CAT, a critical enzyme within the antioxidant mechanism, particularly in dealing with H2O2 by catalyzing its decomposition into water and oxygen, thereby mitigating its accumulation. GPx, another crucial enzyme in the antioxidant mechanism, aids in the conversion of hydrogen peroxide into water and corresponding alcohols. Anti-inflammatory; The hydroalcoholic extract obtained from the aerial parts of F. angulata demonstrates promising anti-inflammatory effects, as evidenced by a reduction in the activity of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). Additionally, there is a notable decrease in C-reactive protein (CRP) levels, while IL-10 shows a significant increase when combining aerobic exercise with an aquatic extract. Hepatoprotective; The hepatoprotective properties exhibited by extracts and purified compounds from this genus are often associated with their anti-inflammatory and antioxidant actions. For instance, the EO derived from F. galbanifera has been shown to inhibit the expression of cytokines IL-1β, IL-6, and inducible nitric oxide synthase (iNOS). Similarly, the MeOH extract of F. angulata has been found to increase the levels of CAT, GPx, and SOD. Furthermore, the hydroalcoholic extract of F. angulata has been demonstrated to reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and MDA in liver tissue. Additionally, umbelliferone, a compound found in these plants, has been shown to inhibit the pro-inflammatory cytokine TNF-α and reduce IL-6 and MDA levels, while also increasing the activity of SOD and GPx